The Gram-positive bacterium Staphylococcus aureus is a major human pathogen (Lowy, 1998. New Engl. J. Med. 339:520-532). S. aureus causes numerous infections including acute skin abscesses (pimples, boils, styes, furunculosis) and invasive infections (pneumonia, mastitis, phlebitis, meningitis, urinary tract infections, osteomyelitis), as well as life-threatening bacteremias and endocarditis. S. aureus is a major pathogen in nosocomial infections, and in infections in patients with indwelling medical devices. S. aureus is also a major pathogen in infections of wounds, including infected diabetic foot ulcers, as well as in burn wounds. S. aureus can also cause toxin-mediated infections including food poisoning and toxic shock syndrome. Over the past 20 years, the frequencies of both nosocomial and community-acquired S. aureus infections has been steadily increasing (Stevens, 2003. Curr. Opin. Infect. Dis. 16:189-191). In addition, numerous multidrug-resistant strains of S. aureus have emerged in recent years (Bal & Gould, 2005. Expert Opin. Pharmacother. 6:2257-2269). These include methicillin-resistant S. aureus (MRSA), which are resistant to all penicillinase-resistant penicillins and cephalosporins (Lowy, 1998. New Engl. J. Med. 339:520-532). Infections caused by MRSA are commonly treated with vancomycin (Pope & Roecker, 2007. Expert Opin. Pharmacother. 8:1245-1261). Recently, however, vancomycin-resistant S. aureus (VRSA) strains have been isolated (Whitener et al., 2004. Clin. Infect. Dis. 38:1049-1055). In addition, S. aureus strains that exhibit resistance to intermediate levels of vancomycin (vancomycin-intermediate S. aureus or VISA) have been isolated (Centers for Disease Control and Prevention, 1997. MMWR Morb. Mortal. Wkly. Rep. 46:624-626). The percentage of S. aureus infections caused by MRSA, VRSA and VISA strains has been increasing (Lodise & McKinnon, 2007. Pharmacother. 27:2002-2012). Infections caused by MRSA, VRSA and VISA strains are often more severe, more easily transmitted, and more difficult to treat, than are infection caused by methicillin-sensitive S. aureus (MSSA) strains (Tristan et al., 2007. J. Hosp. Infect. 65 Suppl 2:105-109). Also, multidrug-resistance may eventually lead to the evolution of S. aureus strains that are resistant to all known antibiotics. New methods for treating and preventing S. aureus infections are urgently needed.
S. aureus is the leading cause of hospital-acquired infections. The federal Centers for Disease Control and Prevention estimates that in 2006 one in 22 hospitalized patients will experience a hospital-acquired infection, resulting in a total of 1.7 million infections and 99,000 deaths (Sack, 2007. New York Times July 27, p. 1). These nosocomial infections account for a significant portion of healthcare expenditures in the United States (Lodise & McKinnon, 2007. Pharmacother. 27:2002-2012). People who are at a higher risk for S. aureus infections include hospitalized patients, older patients, patients with type 1 diabetes, intravenous drug users, patients undergoing hemodialysis, surgical patients, HIV patients, patients with intravascular devices, patients with prosthetic heart valves, patients taking immunosuppressive drugs, and patients with defective leukocyte function. The large number of susceptible patients and the high number of nosocomial infections and deaths underscores the need for improved methods for treating and preventing S. aureus infections.
S. aureus is a natural commensal bacterium that colonizes the anterior nares of approximately 30 to 50 percent of healthy adults. Infection results when a breach in the mucosal barrier or skin allows bacterial cells access to the underlying tissues or to the bloodstream (Lowy, 1998. New Engl. J. Med. 339:520-532). Sites of infection are usually colonized by bacteria from the patient's own nasal reservoir, from contact with an infected patient, or from exposure to the transiently-colonized hands of healthcare workers. Previous studies have shown that eradication of S. aureus nasal carriage results in a decrease in the rate of S. aureus nosocomial infections (Kallen et al., 2005. Infect. Control Hosp. Epidemiol. 26:916-922). Mupirocin cream, applied topically to the nares, has been shown to effectively reduce S. aureus nasal carriage (Bertino, 1997. Amer. J. Health Systems Pharm. 54:2185-2191). However, mupirocin cream needs to be administered 3 times per day for 5 days, and mupirocin-resistant MSSA and MRSA strains have been identified (Kresken et al., 2004. Int. J. Antimicrob. Agents 23:577-581; Hurdle et al., 2005. J. Antimicrob. Chemother. 56:1166-1168). Therefore, there is a need for a method for eradicating S. aureus nasal carriage that is more efficient and less susceptible to the evolution of antimicrobial resistance.
S. aureus is known for its ability to form biofilms, which are defined as communities of bacteria, encased in a self-synthesized extracellular polymeric matrix, growing attached to a biotic or abiotic surface (Gotz, 2002. Mol. Microbiol. 43:1367-1378). Evidence suggests that biofilm formation plays a role in S. aureus wound infections (Akiyama et al., 1996. J. Dermatol. Sci. 11:234-238) and osteomyelitis (Buxton et al., 1987. J. Infect. Dis. 156:942-946). Biofilm formation may also play a role in other localized S. aureus infections. Biofilms that form on tissues or medical devices are extremely difficult to eradicate because the biofilm mode of growth protects bacterial cells from killing by antibiotics and host defenses (Fux et al., 2005. Trends Microbiol. 13:34-40). Therefore, there is a need for anti-infective therapies that can disperse S. aureus biofilms and kill biofilm-embedded S. aureus bacteria.